title: Estrogen-related receptor gamma induces cardiac hypertrophy by activating GATA4.
abstract: Estrogen-related receptor gamma (ERRγ) is an orphan nuclear receptor that has biological roles mainly in metabolism and that controls metabolic switching in perinatal heart. In adult heart diseases, however, the functional roles of ERRγ have not yet been elucidated. In the present study, we aimed to characterize the role of ERRγ in cardiac hypertrophy. The functional roles of ERRγ in the development of cardiac hypertrophy were examined in primary cultured cardiomyocytes and in animal models. ERRγ expression was increased in hearts from human hypertrophic cardiomyopathy patients and in both cellular and animal models of cardiac hypertrophy. Transgenic overexpression in mouse heart as well as forced expression of ERRγ in cardiomyocytes induced hypertrophic phenotypes. Knock-down of ERRγ blocked agonist-induced hypertrophic phenotypes. ERRγ bound directly to the proximal ERR-responsive element in the GATA4 promoter in a sequence-specific manner and thereby induced transcription. ERRγ-induced hypertrophy was blocked by inhibition of GATA4. GSK-5182, an inverse agonist of ERRγ, completely blocked cardiac hypertrophy in cardiomyocytes. It also prevented aortic banding-induced cardiac hypertrophy and fibrosis in mouse heart. These findings demonstrate a novel ERRγ/GATA4 signal cascade in the development of cardiac hypertrophy and suggest GSK-5182 as a possible therapeutic.
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea.
authors.forename: Duk-Hwa
authors.initials: DH
authors.lastname: Kwon
authors.forename: Gwang Hyeon
authors.initials: GH
authors.lastname: Eom
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Nam
authors.forename: Young Kuk
authors.initials: YK
authors.lastname: Cho
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Koo
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Nam
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
mesh_terms: D000328:Adult; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001483:Base Sequence; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D054314:Drug Inverse Agonism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: C490917:ESRRG protein, human; C490916:Esrrg protein, mouse; D050991:GATA4 Transcription Factor; C583041:GSK5182; D011960:Receptors, Estrogen; D013629:Tamoxifen; D009320:Atrial Natriuretic Factor
keywords: Cardiac hypertrophy; Estrogen-related receptor gamma; GATA4; GSK-5182; Orphan nuclear receptor